title: Mutation mapping of apolipoprotein A-I structure assisted with the putative cholesterol recognition regions.
abstract: Twenty-nine from 52 missense mutations in apoA-I gene are predicted to be deleterious by both SIFT and PolyPhen-2 algorithms. Among those, eight mutations with a prominent change in structure stability as modeled by the SDM tool for both lipid-free (Mei and Atkinson (2011) PDB ID: 3R2P) and HDL-bound (Wu et al. (2009) PDB ID: 3K2S) apoA-I, are referred as structural. The remaining mutations with a preferential location in a long intrinsically disordered region, predicted by the SPINE-D and DNdisorder tools, may influence the functional sites. Among structural mutations, five amyloidosis-only-related mutations, significant in a lipid-free structure, are located in 1-90 region. Six amyloidosis- and hypoalphalipoproteinemia-associated mutations, differently significant in two chains of lipid-bound apoA-I, are distributed among the N-domain. Six cholesterol recognition putative motifs (5 CRAC/1 CCM) in apoA-I structure are suggested to interact with cholesterol. Among those, the K40-W50 partially conserved CCM sequence with a putative recognition feature, predicted by the MoRF tool, may underlie cholesterol binding to lipid-free apoA-I, the binding triggering the disorder-to-order transition within MoRF. Thus, the impairment of helix formation and accelerated protein aggregation may underlie the amyloidogenic effect of W50R substitution. Also, D102H substitution in conserved CRAC2 V97-K106 sequence may be harmful in reverse cholesterol transport. With PDBe Motifs and Sites algorithm, cholesterol is a ligand for L101, F104 and W108 residues in HDL-bound apoA-I. The influence of specific mutation on apoA-I structure and mutated apolipoprotein switch between different pathologies is suggested to depend on the surrounding phase properties.
authors.affiliation: National Research Centre for Preventive Medicine, 10, Petroverigsky Street, 101990 Moscow, Russia. Electronic address: dergunov@img.ras.ru.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Dergunov
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000235:genetics*; D001665:Binding Sites; D002784:Cholesterol / Q000737:chemistry*; D002942:Circular Dichroism; D006801:Humans; D052456:Hypoalphalipoproteinemias / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008075:Lipoproteins, HDL / Q000737:chemistry*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D002784:Cholesterol
keywords: Amyloidosis; Apolipoprotein A-I; CCM; CRAC; HDL; HGMD; Human Genome Mutation Database; Hypoalphalipoproteinemia; IDR; Missense mutation; MoRF; RCT; Reverse cholesterol transport; SNP; Structure prediction; apoA-I; apolipoprotein A-I; cholesterol consensus motif; cholesterol recognition/interaction amino acid consensus; high density lipoproteins; intrinsically disordered regions; molecular recognition feature; reverse cholesterol transport; single nucleotide polymorphism